What new bike?

Go for the Cannondale. It really impressed you and they are a solid brand and it's only a bit over budget.

I think that Welsh Boy is right, buy with the heart, the one that excites you the most.  

I’ve thought about bespoke, but never been able to justify it.  I believe (but have no evidence), that unless you’re a funny shape, or have particular needs, you should be able to get an off the peg to fit perfectly, but it would be special, and so pass the ‘heart’ test.

I’ve enjoyed my carbon Defy, it is fast and comfortable.

I’ve had a steel (Equilibrium disc, 725, so a bit low end compared to your budget) commuter, and although I’ve had my fastest rides on it, it’s not as stiff, or as comfortable as the Defy.

 Last year I came across a Kinesis GFTI Disc for sale, but decided that it was too expensive for no 6.  I still kept looking it it though, and when the price was reduced I went and tried it.  As soon as I did, that was it.  I use it pretty much daily on long commutes, and I’ve done a few longer rides (one 200k+) as well, but I can’t bring myself to sell the Defy either!

So (as always) it depends what you want.

The Defy is great for unloaded rides, with an Arkel Radonneur can carry a bit of stuff, and Crud Catchers do mudguard duty.  The GFTI is probably more comfortable and feels as stiff and responsive, but I’ve a (Ti) rack on the back, so I can carry a reasonable load as well, and I’ve full guards, which I am regularly grateful for.  If I had just one it would be the Kinesis, and in your shoes I’d also look at Laverack and Reilly as they get good write-ups.

Electronic shifting is on my list for a forthcoming upgrade to the Kinesis.  I’m leaning towards Shimano, but only due to battery life as I’ve found Sram and Shimano equally easy to use.

Good luck with your search.

Agree with Davethegraveraver, custom titanium all the way for me with plenty of Campagnolo hanging off it.

Last ever bike? 5 grand plus budget? Has to be titanium or a custom build. The bikes you mention are all great, but a bit ubiquitous. I can't really tell a 1500 quid Synapse from a 5k one, if it was my money I'd want something a bit different, a bit special.
You should also look at Trek Domane and Spesh Roubaix if you're looking at Synapse and Defy.
Evans are a good retailer for demos, you'll have to book it and leave your details, but they have a bigger range than most retailers and were happy to let me try several different machines

Yeah for that money and for a “forever” bike, I’d go hand built bespoke. So something titanium or high end steel. That way it’ll never look dated and you can just update any componentry as the tech changes (12 speed?). You could have a couple of nice wheelsets and not blow half your budget on the groupset. 

Nice list, I'm sure you would enjoy any of those :-).  Personally if I buy a forever bike it will be titanium have have loads of tyre clearance and mounts for gauards and a rack.  Then I'd probably have a couple of wheel sets, one for road and one for tow path/mild off-road.  Then I'd probably never use the road set anyway as the others are likey to be more comfortable.

Tyre clearance? Opens possibly of routes with bump bumps yet also allows thinner tyre usage.

I echo all of the above I don't think you'd have buyers regret getting any of them.. however I'd suggest as you've suggested that this bike should last you for a bit then get the best frame possible for the money. To me that looks like the High Mod Cannondale or the Defy Advanced SL.

You can get 10% off the price of the Giant by being nice to my local LBS and I suspect if you haggled hard enough you could upgrade the SLR1 wheels to SLR0 wheels and come within your budget.(Giant's top end wheels are VERY VERY good and you'll save £ in the long run if you upgrade from the oft).

They are all very good bike (the Canyon and Cannondale especially). Welsh Boy is right, go with whichever excites you the most!

Buy with your heart, which bike makes you want to ride it even when the weather is poor.  A bike which was bought on the recommendation of a total stranger on an internet forum which sits in the shed because you dont really want to ride it is a poor purchase.  The bike which makes you want to go out even in the wet, miserable, cold British summer and return with a smile on your face is  good purchase.  Go with your heart, not a stranger's recommendation (and I predict that all the recommendations you get for one bike over another will be made by people who have not made a direct comparison of the 3 you mention so how much use is that opinion anyway?)